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Association of rare chymotrypsinogen C (CTRC) gene variations in patients with idiopathic chronic pancreatitis

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Abstract

Extensive genetic studies of chronic pancreatitis over the past decade have highlighted the importance of a tightly regulated balance between activation and inactivation of trypsin within the pancreas to disease susceptibility and resistance. The recent identification of chymotrypsin C (CTRC) as enzyme Y, which was proposed to protect the pancreas by degrading prematurely activated trypsinogen within the pancreas 20 years ago, made CTRC an excellent candidate gene for disease-association studies. Here, we analyzed all eight exons of the CTRC gene for conventional genetic variants and copy number variations (CNVs) by direct sequencing and quantitative fluorescent multiplex PCR, respectively, in a total of 287 French white patients (idiopathic × 216; familial × 42; hereditary × 29). While no CNVs were found in any of the 287 subjects, 20 conventional variations including a nonsense mutation (p.W55X), a microdeletion mutation (p.K247_R254del) and nine missense mutations were found in the 216 patients with idiopathic chronic pancreatitis (ICP). Except for two common polymorphisms, all the remaining 18 mutational events represent rare variations, with a minor allele frequency of 0–0.3% in the control population. All these rare variants were always found more frequently in the ICP patients than in the controls, and their combined frequency in the ICP patients (26/216; 12.0%) is significantly different from that in the controls (4/350; 1.1%) (OR = 11.8 [3.9–40.6]), χ 2 = 31.58, P < 10−6). This genetic finding, when considered in the perceived role of CTRC in eliminating prematurely activated trypsin, indicated that CTRC is a new pancreatitis susceptibility gene.

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Acknowledgments

This work was supported by the INSERM (Institut National de la Santé et de la Recherche Médicale), the PICRI (Partenariats Institutions Citoyens pour la Recherche et l’Innovation) project, the GIS Institut des Maladies Rares (project no. A07092NS), and the APCH (Association des Pancréatites Chroniques Héréditaires), France. E.M. is a PhD student supported by the Programme Hospitalier de Recherche Clinique (grant PHRC R 08-04), France.

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Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale (INSERM), U613, 29220, Brest, France

    Emmanuelle Masson, Jian-Min Chen, Virginie Scotet, Cédric Le Maréchal & Claude Férec

  2. Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale (UBO), 29238, Brest, France

    Emmanuelle Masson, Jian-Min Chen, Virginie Scotet, Cédric Le Maréchal & Claude Férec

  3. Etablissement Français du Sang (EFS) – Bretagne, 46 rue Félix Le Dantec, 29220, Brest, France

    Emmanuelle Masson, Jian-Min Chen, Virginie Scotet, Cédric Le Maréchal & Claude Férec

  4. Centre Hospitalier Universitaire (CHU) Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire et d’Histocompatibilité, 29220, Brest, France

    Cédric Le Maréchal & Claude Férec

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  1. Emmanuelle Masson
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  2. Jian-Min Chen
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Correspondence to Jian-Min Chen.

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Masson, E., Chen, JM., Scotet, V. et al. Association of rare chymotrypsinogen C (CTRC) gene variations in patients with idiopathic chronic pancreatitis. Hum Genet 123, 83–91 (2008). https://doi.org/10.1007/s00439-007-0459-3

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